CN113214321B - Preparation method of minodronate E crystal form - Google Patents
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- CN113214321B CN113214321B CN202110299656.8A CN202110299656A CN113214321B CN 113214321 B CN113214321 B CN 113214321B CN 202110299656 A CN202110299656 A CN 202110299656A CN 113214321 B CN113214321 B CN 113214321B
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- 239000013078 crystal Substances 0.000 title claims abstract description 121
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229950011129 minodronic acid Drugs 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000002425 crystallisation Methods 0.000 claims abstract description 39
- 230000008025 crystallization Effects 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000010907 mechanical stirring Methods 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 18
- 238000003760 magnetic stirring Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000002411 thermogravimetry Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 abstract description 12
- 230000006698 induction Effects 0.000 abstract description 7
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 19
- 238000000113 differential scanning calorimetry Methods 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 238000001757 thermogravimetry curve Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- GPAPAOGRNKUFGH-UHFFFAOYSA-N (1-hydroxy-2-imidazo[1,2-a]pyridin-3-yl-1-phosphonoethyl)phosphonic acid;hydrate Chemical compound O.C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 GPAPAOGRNKUFGH-UHFFFAOYSA-N 0.000 description 2
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 2
- VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- -1 nitrogen-containing aromatic heterocyclic bisphosphonate Chemical class 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of minodronate E crystal form, which adopts a seed crystal induction mode to control the mass ratio of seed crystal to minodronate, can obtain a large batch (more than kilogram level) of stable minodronate E crystal form in the conventional mechanical stirring crystallization process, has high yield and purity, reaches 90 percent of yield and 99 percent of purity, almost does not contain D crystal form, has simple preparation method and mild reaction condition, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a minodronic acid E crystal form.
Background
Minodronic Acid (Minodronic Acid) is a third-generation nitrogen-containing aromatic heterocyclic bisphosphonate, developed by nippon xiaoyu pharmaceutical industry co-Ltd and Japanese Astellas (combined preparation in 4-month mountain in 2005 and Tanze preparation, new company named Astellas) pharmaceutical Co., Ltd, filed in 7-month in 2006 with the same province of Kyoho, first approved to the market in 1-21-month in 2009, and sold under the trade names of Astelas
(Xiaoye drug) and
(Astellas pharmaceuticals). Minodronic acid is a novel heterocyclic bisphosphonic acid compound, is used for treating osteoporosis and hyperemia caused by osteoporosis and malignant tumors, inhibits the bone absorption of osteoclasts and reduces bone turnover by inhibiting the activity of farnesyl pyrophosphate (FPP) synthetase in the osteoclasts, and has the effect of preventing and treating osteoporosis. Minodronic acid has the chemical name (1-hydroxy-2- [ imidazo (1,2-a) pyridin-3-yl)]Ethylene) bisphosphonic acid monohydrateA compound having the formula:
minodronic acid is disclosed in the japanese intra-mountain pharmaceutical patent US5480875 in various crystalline forms. Of the various hydrated forms of minodronate, the monohydrate form is the most stable form for solid pharmaceutical formulations. The minodronate monohydrate comprises two crystal forms D and E, has the same X-ray powder diffraction spectrum, and has maximum water loss peak temperatures of 135-149 ℃ (crystal form D) and 160-170 ℃ (crystal form E) in a DSC thermogravimetric analysis spectrogram respectively.
The property of the D, E crystal form is further described in japanese intrashan pharmaceutical patent JP2016104714, and the E crystal form has higher temperature loss than the D crystal form, has better thermodynamic stability, and has greater advantages in solid preparations. The D crystal form or the D, E mixed crystal form can be converted into the E crystal form in the physical processes of friction, crushing and the like, which shows that the E crystal form is a more stable crystal form.
A preparation method of E-form minodronic acid is reported in japanese intra-mountain pharmaceutical patent US5480875, but the method is only suitable for preparing E-form minodronic acid (in grams) in laboratory scale, and the specific preparation method is as follows: and under the condition that no obvious vortex exists on the surface of the solution, slowly performing magnetic stirring precipitation to obtain the E crystal form minodronic acid. It is also reported in the patent that minodronic acid in form D is suitable for preparation on an industrial scale (in kilograms) by mechanical stirring to form a precipitate. Experiments show that only the D crystal form of minodronic acid can be obtained by a conventional mechanical stirring crystallization mode.
Therefore, it is important to develop a preparation method suitable for industrial grade (in kilogram) minodronate E crystal form without magnetic stirring crystallization.
Disclosure of Invention
The invention aims to provide a preparation method of minodronate E crystal form based on the prior art, and solves the problem that the E crystal form minodronate is difficult to industrially produce on a large scale due to harsh preparation conditions.
The technical scheme of the invention is as follows:
a preparation method of minodronate E crystal form comprises the following steps:
(1) starting mechanical stirring, mixing minodronic acid with an organic solvent, and completely dissolving minodronic acid in the solvent at the temperature of 90-95 ℃;
(2) cooling the mixed solution obtained in the step (1) to 30-60 ℃, adding seed crystals, and continuously stirring for 1-3 hours; the seed crystal is of a minodronate E crystal form; wherein the mass of the seed crystal is 2-20% of that of the minodronic acid;
(3) and (3) cooling the mixed solution obtained in the step (2) to 0-30 ℃, stirring and crystallizing for 8-16 h, filtering after crystallization is finished, and drying in vacuum to obtain the minodronic acid E crystal form.
The crystal seed adopted by the invention is a minodronate E crystal form, and is obtained by magnetic stirring crystallization in a laboratory scale. In a preferred embodiment, the seed crystal is prepared as follows: starting magnetic stirring, mixing minodronic acid with 1mol/L hydrochloric acid aqueous solution, completely dissolving minodronic acid at 90-95 ℃, cooling to 0-30 ℃, stirring for crystallization for 6-10 h, filtering after crystallization is finished, and drying in vacuum to obtain the seed crystal.
In a more preferred embodiment, the method for preparing the seed crystal comprises the following more detailed steps: starting magnetic stirring, mixing 180g of minodronic acid with 2700mL of 1mol/L hydrochloric acid aqueous solution, completely dissolving the minodronic acid at 90-95 ℃, cooling to 10-20 ℃, stirring for crystallization for 8 hours, filtering after crystallization is finished, and drying in vacuum to obtain the seed crystal.
Further, the vacuum drying conditions are as follows: the drying temperature is 40-60 ℃, and the drying pressure is-0.08 to-0.1 MPa; further preferably, the drying temperature is 50 ℃ and the drying pressure is-0.09 MPa.
The minodronate monohydrate comprises two crystal forms D and E, wherein the crystal form D or the mixed crystal form D, E can be converted into the crystal form E in the physical processes of friction, crushing and the like, which shows that the crystal form E is a more stable crystal form. However, the preparation condition of the crystal form E is harsh, so that the crystal form E is only suitable for magnetic stirring preparation in a laboratory scale, and industrial large-scale production is difficult.
Aiming at one problem, the invention tries to prepare the minodronate E crystal form on a large scale by a plurality of methods under the condition of mechanical stirring, for example, seed crystal induction, a specific solvent, and the temperature and time of crystallization, except for the mode of inducing crystallization, other modes have poor effect, and basically the D crystal form is obtained. Even if the E crystal form seed is adopted for induction, the dosage of the seed and the crystal seed is strictly controlled in the process of seed induction. Too high or too low an amount of seed crystals both reduces the yield and purity of the minodronate E crystal form. The excessive dosage of the seed crystal can cause the crystal to explode and separate out, and D, E mixed crystals are obtained; the amount of the seed crystal is too small, the induced crystallization effect is poor, and D, E mixed crystals are also obtained.
In the present invention, the mass of the seed crystal is 2 to 20% of the mass of the minodronic acid at the time of seed crystal induction, and may be, but not limited to, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 15%, 18%, or 20%, and in order to obtain a preferable effect, the mass of the seed crystal is 3 to 10% of the mass of the minodronic acid, and further, the mass of the seed crystal is 5% of the mass of the minodronic acid.
In the step (2), the temperature of the seed crystal needs to be controlled when the seed crystal is added, and the temperature is too high or too low to be beneficial to the induction effect of the seed crystal, so that the yield and the purity of the minodronate E crystal form are influenced. When the temperature is over high, part of the seed crystals are redissolved to obtain D, E mixed crystals; when the temperature is too low, part of the D crystal form is separated out, and D, E mixed crystals are also obtained.
For example, in the step (2), the mixed solution obtained in the step (1) is cooled to 30-60 ℃, and then seed crystals are added. In a preferable scheme, before adding the seed crystal, the temperature is reduced to 40-50 ℃.
Further, in the step (2), after the seed crystal is added, stirring is continued for 1-3 h, preferably, after the seed crystal is added, stirring is continued for 2 h.
For the present invention, in step (1), the solvent is methanol, ethanol, ethyl acetate, acetone or 1mol/L aqueous hydrochloric acid, preferably, the solvent is 1mol/L aqueous hydrochloric acid.
In a preferable scheme, in the step (3), the mixed solution obtained in the step (2) is cooled to 10-20 ℃, and stirred for crystallization for 10-12 hours.
Further, in the step (3), the vacuum drying conditions are as follows: the drying temperature is 40-60 ℃, and the drying pressure is-0.08 to-0.1 MPa; further preferably, the drying temperature is 50 ℃ and the drying pressure is-0.09 MPa.
The minodronate E crystal form prepared by the method disclosed by the invention has the maximum water loss peak temperature of 160-170 ℃ in a DSC thermogravimetric analysis spectrogram.
The minodronate E crystal form prepared by the method has diffraction peaks at 9.41 +/-0.2 degrees, 10.18 +/-0.2 degrees, 11.91 +/-0.2 degrees, 12.29 +/-0.2 degrees, 13.71 +/-0.2 degrees, 15.59 +/-0.2 degrees, 16.25 +/-0.2 degrees, 17.09 +/-0.2 degrees, 18.35 +/-0.2 degrees, 18.86 +/-0.2 degrees, 20.14 +/-0.2 degrees, 20.44 +/-0.2 degrees, 22.94 +/-0.2 degrees, 24.00 +/-0.2 degrees, 24.33 +/-0.2 degrees, 24.79 +/-0.2 degrees, 25.90 +/-0.2 degrees, 26.38 +/-0.2 degrees, 27.16 +/-0.2 degrees, 27.71 +/-0.2 degrees, 28.06 +/-0.2 degrees and 28.90 +/-0.2 degrees by using Cu-Kalpha radiation and X-ray powder diffraction (X-RPD) expressed by an angle of 2 theta.
The invention relates to an X-ray powder diffraction spectrum detection method, which comprises the following steps: the polycrystalline X-ray Diffractometer is a D8 advanced X-ray Diffractometer, and the operation method is Cu-Kalpha diffraction (wavelet 11.5406A degrees, wavelet 21.5443A degrees, Generator 40KV degrees and Generator 40mA), the scanning angle range is 3-40 degrees, the scanning step is 0.02 degree, and the step time is 0.3 s.
The DSC detection method comprises the following steps: a DSC Q2000 differential scanning calorimeter is used, the heating range is 30-300 ℃, and the heating speed is 10 ℃/min.
By adopting the technical scheme of the invention, the advantages are as follows:
the method adopts a seed crystal induction mode, controls the mass ratio of the seed crystal to the minodronic acid, can obtain a large amount (more than kilogram level) of stable minodronic acid E crystal forms in the conventional mechanical stirring crystallization process, has high yield and purity, the yield reaches 90 percent, the purity reaches 99 percent, and the minodronic acid E crystal forms hardly contain D crystal forms, has simple preparation method and mild reaction conditions, and is suitable for industrial large-scale production.
Drawings
FIG. 1 is a differential scanning calorimetry thermogram of a crystalline minodronate E seed prepared in example 1;
FIG. 2 is a differential scanning calorimetry thermogram of the crystalline form E of minodronate prepared in example 1;
FIG. 3 is an X-ray powder diffraction pattern of minodronate E crystalline form prepared in example 1;
fig. 4 is an HPLC profile of crystalline minodronate E prepared in example 1;
fig. 5 is a differential scanning calorimetry thermogram of the crystalline form E of minodronate prepared in comparative example 1;
fig. 6 is a differential scanning calorimetry thermogram of the crystalline form D of minodronate prepared in comparative example 2;
FIG. 7 is a differential scanning calorimetry thermogram of a minodronic acid D, E mixed crystal prepared in comparative example 3;
FIG. 8 is a differential scanning calorimetry thermogram of a minodronic acid D, E mixed crystal prepared in comparative example 4;
FIG. 9 is a differential scanning calorimetry thermogram of the minodronic acid D, E mixed crystal prepared in comparative example 5;
FIG. 10 is a differential scanning calorimetry thermogram of a minodronic acid D, E mixed crystal prepared in comparative example 6.
Detailed Description
The process for the preparation of the crystalline form E of minodronate according to the invention is further illustrated by the following examples, which are not intended to limit the invention in any way, in conjunction with the attached drawings.
Example 1:
preparation of crystal seed of crystal form E:
adding 180.00g (0.53mol) of minodronic acid and 2700mL of 1mol/L hydrochloric acid aqueous solution into a 3L reaction bottle, uniformly mixing under magnetic stirring, heating to 90-95 ℃, cooling to 10-20 ℃ after solids are completely dissolved, and crystallizing for 8 hours under magnetic stirring. After crystallization, the mixture was filtered by suction, and the obtained filter cake was vacuum-dried at 50 ℃ and-0.09 MPa to obtain 160.40g of a solid with a yield of 89.11%. As can be seen from FIG. 1, the differential scanning calorimetry has the maximum water loss endothermic peak at 150-170 ℃, which indicates that the seed crystal is of the E crystal form.
Preparation of minodronate E crystal form:
adding 45L of 1mol/L hydrochloric acid aqueous solution into a 100L reaction kettle, starting mechanical stirring, rotating at the speed of 200r/min, adding 3.00kg (8.82mol) of minodronic acid, heating to 90-95 ℃, cooling to 40-50 ℃ after the solid is completely dissolved, adding 0.15kg (0.44mol) of seed crystal, and stirring for 2 hours. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, carrying out suction filtration, and carrying out vacuum drying on the obtained filter cake at 50 ℃ and-0.09 MPa to obtain 2.98kg of minodronate E crystal form, wherein the yield is 94.60 percent, and the purity is 99.77 percent. As can be seen from FIG. 2, the differential scanning calorimetry has the maximum water loss endothermic peak at 150-170 ℃, which indicates that the product is of E crystal form. The X-ray powder diffraction spectrum is shown in FIG. 3, and the HPLC spectrum is shown in FIG. 4.
Example 2:
preparation of minodronate E crystal form:
adding 60L of ethanol into a 100L reaction kettle, starting mechanical stirring, rotating at the speed of 150r/min, adding 2.00kg (5.88mol) of minodronic acid, heating to 90-95 ℃, cooling to 50-60 ℃ after the solid is completely dissolved, adding 0.06kg (0.18mol) of the seed crystal prepared in example 1, and stirring for 2 hours. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, suction filtration is carried out, and the obtained filter cake is vacuum dried under the conditions of 50 ℃ and-0.09 MPa, so as to obtain 1.94kg of minodronate E crystal form, wherein the yield is 94.17 percent, and the purity is 99.90 percent.
Example 3:
preparation of minodronate E crystal form:
adding 30L of methanol into a 100L reaction kettle, starting mechanical stirring, rotating at the speed of 200r/min, adding 1.50kg (4.41mol) of minodronic acid, heating to 90-95 ℃, cooling to 50-60 ℃ after the solid is completely dissolved, adding 0.15kg (0.44mol) of the seed crystal prepared in example 1, and stirring for 2 hours. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 1.57kg of minodronate E crystal form, wherein the yield is 95.15% and the purity is 99.82%.
Comparative example 1:
reference is made to the magnetic stirring crystallization method reported in the original patent US5480875 to prepare minodronic acid E crystal form
4.00g (0.01mol) of minodronic acid and 150.0mL of 1mol/L hydrochloric acid aqueous solution are added into a 250mL reaction bottle, slowly and magnetically stirred until no vortex appears on the liquid surface, and the temperature is raised to reflux to completely dissolve the solid. Then, slowly cooling to 20-30 ℃, and crystallizing for 15 hours under magnetic stirring. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 3.31g of solid, wherein the yield is 82.75 percent, and the purity is 98.92 percent. As can be seen from FIG. 5, the differential scanning calorimetry has the maximum endothermic peak of water loss at 150-170 ℃, which indicates that the product is of the E crystal form.
Comparative example 2:
reference is made to the mechanical stirring crystallization method reported in the original patent US5480875 for preparing minodronic acid D crystal form
To a 500mL reaction flask were added 10.00g (0.03mol) of minodronic acid and 400.0mL of 1mol/L aqueous hydrochloric acid, mechanical stirring was turned on, and the temperature was raised to reflux to completely dissolve the solid. Then, slowly cooling to 20-30 ℃, stirring and crystallizing for 15 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 8.82g of solid, wherein the yield is 88.20 percent and the purity is 98.86 percent. As can be seen from FIG. 6, the differential scanning calorimetry has the maximum water loss endothermic peak at 130-150 ℃, which indicates that the product is in the D crystal form.
Comparative example 3:
adding 600mL of 1mol/L hydrochloric acid aqueous solution into a 1000mL reaction bottle, starting mechanical stirring, rotating at a speed of 200r/min, adding 20.00g (0.06mol) of minodronic acid, heating to 90-95 ℃, cooling to 50-60 ℃ after the solid is completely dissolved, adding 6.00g (0.02mol) of the seed crystal prepared in example 1, and stirring for 2 h. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 24.94g of solid, wherein the yield is 95.92% and the purity is 99.60%. As can be seen from FIG. 7, the differential scanning calorimetry has a broad endothermic peak of water loss at 130-170 ℃, indicating that the product is D, E mixed crystal.
Comparative example 4:
adding 600mL of 1mol/L hydrochloric acid aqueous solution into a 1000mL reaction bottle, starting mechanical stirring, rotating at a speed of 200r/min, adding 20.00g (0.06mol) of minodronic acid, heating to 90-95 ℃, cooling to 50-60 ℃ after the solid is completely dissolved, adding 0.40g (0.001mol) of the seed crystal prepared in example 1, and stirring for 2 h. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 18.30g of solid, wherein the yield is 89.71% and the purity is 99.68%. As can be seen from FIG. 8, the differential scanning calorimetry has a broad endothermic peak of water loss at 130-170 ℃, indicating that the product is D, E mixed crystal.
Comparative example 5:
adding 300mL of 1mol/L hydrochloric acid aqueous solution into a 500mL reaction bottle, starting mechanical stirring, rotating at a speed of 200r/min, adding 10.00g (0.03mol) of minodronic acid, heating to 90-95 ℃, cooling to 70-75 ℃ after the solid is completely dissolved, adding 0.50g (0.002mol) of the seed crystal prepared in example 1, and stirring for 2 hours. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 9.74g of solid, wherein the yield is 92.76% and the purity is 99.70%. As can be seen from FIG. 9, the differential scanning calorimetry has a broad endothermic peak of water loss at 130-170 ℃, indicating that the product is D, E mixed crystal.
Comparative example 6:
adding 300mL of 1mol/L hydrochloric acid aqueous solution into a 500mL reaction bottle, starting mechanical stirring, rotating at a speed of 200r/min, adding 10.00g (0.03mol) of minodronic acid, heating to 90-95 ℃, cooling to 20-30 ℃ after the solid is completely dissolved, adding 0.50g (0.002mol) of the seed crystal prepared in example 1, and stirring for 2 hours. Then, cooling to 10-20 ℃, and stirring for crystallization for 12 hours. After crystallization, the mixture is filtered, and the obtained filter cake is dried in vacuum at 50 ℃ and-0.09 MPa to obtain 9.82g of solid, wherein the yield is 93.52% and the purity is 99.76%. As can be seen from FIG. 10, the differential scanning calorimetry has a broad endothermic peak of water loss at 130-170 ℃, indicating that the product is D, E mixed crystal.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A preparation method of minodronic acid E crystal form is characterized by comprising the following steps:
(1) starting mechanical stirring, mixing minodronic acid with an organic solvent, and completely dissolving minodronic acid in the solvent at the temperature of 90-95 ℃; the organic solvent is methanol or ethanol;
(2) cooling the mixed solution obtained in the step (1) to 30-60 ℃, adding seed crystals, and continuously stirring for 1-3 hours; the seed crystal is of a minodronate E crystal form; the mass of the seed crystal is 2-20% of that of the minodronic acid;
(3) cooling the mixed solution obtained in the step (2) to 0-30 ℃, stirring and crystallizing for 8-16 h, filtering after crystallization is finished, and drying in vacuum to obtain a minodronic acid E crystal form;
wherein, the X-ray powder diffraction of the minodronic acid E crystal form expressed by the angle of 2 theta has diffraction peaks at 9.41 +/-0.2 degrees, 10.18 +/-0.2 degrees, 11.91 +/-0.2 degrees, 12.29 +/-0.2 degrees, 13.71 +/-0.2 degrees, 15.59 +/-0.2 degrees, 16.25 +/-0.2 degrees, 17.09 +/-0.2 degrees, 18.35 +/-0.2 degrees, 18.86 +/-0.2 degrees, 20.14 +/-0.2 degrees, 20.44 +/-0.2 degrees, 22.94 +/-0.2 degrees, 24.00 +/-0.2 degrees, 24.33 +/-0.2 degrees, 24.79 +/-0.2 degrees, 25.90 +/-0.2 degrees, 26.38 +/-0.2 degrees, 27.16 +/-0.2 degrees, 27.71 +/-0.2 degrees, 28.06 +/-0.2 degrees and 28.90 +/-0.2 degrees; the minodronate E crystal form has a maximum water loss peak temperature of 160-170 ℃ in a DSC thermogravimetric analysis spectrogram.
2. The process for preparing crystalline form E of minodronate according to claim 1, characterized in that, in step (2), the seeds are prepared as follows: starting magnetic stirring, mixing minodronic acid with 1mol/L hydrochloric acid aqueous solution, completely dissolving minodronic acid at 90-95 ℃, cooling to 0-30 ℃, stirring for crystallization for 6-10 h, filtering after crystallization is finished, and drying in vacuum to obtain seed crystals.
3. The process for preparing crystalline form E of minodronate according to claim 2, characterized in that, in step (2), the seeds are prepared as follows: starting magnetic stirring, mixing 180g of minodronic acid with 2700mL of 1mol/L hydrochloric acid aqueous solution, completely dissolving the minodronic acid at 90-95 ℃, cooling to 10-20 ℃, stirring for crystallization for 8 hours, filtering after crystallization is finished, and drying in vacuum to obtain the seed crystal.
4. The process for the preparation of crystalline form E of minodronic acid according to claim 1,2 or 3, characterized in that, in step (2), the mass of said seeds is between 3 and 10% of the mass of minodronic acid.
5. The process for preparing crystalline form E of minodronate according to claim 4, characterized in that, in step (2), the mass of said seeds is 5% of the mass of minodronate.
6. The method for preparing crystalline form E of minodronate according to claim 4, wherein in step (2), before the addition of the seed crystal, the temperature is reduced to 40-50 ℃.
7. The process for the preparation of crystalline form E of minodronate according to claim 4, characterized in that, in step (2), stirring is continued for 2h after the addition of the seeds.
8. The method for preparing the minodronate E crystal form according to claim 4, wherein in the step (3), the mixed solution obtained in the step (2) is cooled to 10-20 ℃, and stirred for crystallization for 10-12 hours.
9. The process for the preparation of crystalline form E of minodronate according to claim 4, characterized in that the conditions of vacuum drying are: the drying temperature is 40-60 ℃, and the drying pressure is-0.08 to-0.1 MPa.
10. The process for preparing crystalline form E of minodronate according to claim 9, characterized in that the conditions of vacuum drying are: the drying temperature is 50 ℃, and the drying pressure is-0.09 MPa.
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| US5480875A (en) * | 1992-06-23 | 1996-01-02 | Yamanouchi Pharmaceutical Co., Ltd. | Crystal of monohydrate of heterocyclic bis(phosphonic acid) derivative |
| CN103183709A (en) * | 2011-12-30 | 2013-07-03 | 天津药物研究院 | Minodronic acid new crystal form, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5480875A (en) * | 1992-06-23 | 1996-01-02 | Yamanouchi Pharmaceutical Co., Ltd. | Crystal of monohydrate of heterocyclic bis(phosphonic acid) derivative |
| CN103183709A (en) * | 2011-12-30 | 2013-07-03 | 天津药物研究院 | Minodronic acid new crystal form, preparation method and application |
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